Glaucoma is one of the main causes of blindness in Japan and thus it is a severe problem in the ophthalmologic field. According to a previous investigation, patients of glaucoma were estimated at 3.56% among 40- or more aged people. However, a recent big-scaled investigation discloses that even more people are suffering from glaucoma (cf. the website of the Japanese Ophthalmological Society). Glaucoma is thought to be a disease that the intraocular pressure is raised more than normal and then optic nerve is damaged to become visual field constriction which is one of the main causes of blindness.
Recently, normal tension glaucoma has also been becoming a serious problem. The normal tension glaucoma is a disease whose symptom is the same as glaucoma though the intraocular pressure is within the normal range (ordinarily 21 mmHg or less). And it is becoming clear that the prevalence of the normal tension glaucoma covers a large part of the whole glaucoma.
Thus, the cause of glaucoma, especially normal tension glaucoma is not so clear, though glaucoma is a serious disease including a risk factor of blindness, and the classification thereof is also complicated. Therefore, it has been desired to develop a novel medicament for treating glaucoma which is more useful than a current medicament such as a beta-blocker, a prostaglandin drug, and an alpha-agonist; and especially which is expected to have a different mechanism from those of current medicaments or wherein an active ingredient thereof has a different type of structure.
The carbostyril derivatives of formula (1) or salts thereof and the processes for the preparation thereof are disclosed in JP-63-20235-B. And it is known that the carbostyril derivatives (1) have platelet aggregation inhibition action, phosphodiesterase (PDE) inhibition action, antiulcer, hypotensive action and antiphlogistic action, and are useful as an antithrombotic agent, a drug for improving cerebral circulation, an anti-inflammatory agent, an antiulcer drug, an antihypertensive drug, an antiasthmatic drug, a phosphodiesterase inhibitor, etc.
In addition, Journal of Ocular Pharmacology and Therapeutics (Vol. 14, No. 3, 239-245 (1998)) discloses that the i.v. injection of cilostazol which is one of the above-mentioned carbostyril derivatives can act on optic nerve, and thus it indicates that the carbostyril derivates might be useful for treating glaucoma without any experimental evaluation.
In addition, JP-2003-63965-A discloses an aqueous formulation of cilostazol for injection which includes a cyclodextrin in order to enhance the solubility of cilostazol to water and then allow cilostazol to be a formulation thereof for injection, since the carbostyril derivatives are hard to dissolve in water.